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Werlen G  Hausmann B  Palmer E 《Nature》2000,406(6794):422-426
Positive selection allows thymocytes that recognize an individual's own major histocompatibility complex (self-MHC) molecules to survive and differentiate, whereas negative selection removes overtly self-reactive thymocytes. Although both forms of thymic selection are mediated by the alphabeta T-cell receptor (TCR) and require self-MHC recognition, an important question is whether they are controlled by distinct signalling cascades. We have shown that mutation of an essential motif within the TCR alpha-chain-connecting peptide domain (alpha-CPM) profoundly affects positive but not negative selection. Using transgenic mice expressing a mutant alpha-CPM TCR we examined the contribution of several mitogen-activated protein kinase (MAPK) cascades to thymic selection. Here we show that in thymocytes expressing a mutant alpha-CPM receptor, a positively selecting peptide failed to activate the extracellular signal-regulated kinase (ERK), although other MAPK cascades were induced normally. The defect in ERK activation was associated with impaired recruitment of the activated tyrosine kinases Lck and ZAP-70, phosphorylated forms of the TCR component CD3zeta and the adaptor protein LAT to detergent-insoluble glycolipid-enriched microdomains (DIGs). Therefore, an intact DIG-associated signalosome is essential for sustained ERK activation, which leads to positive selection.  相似文献   

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Bensinger SJ  Tontonoz P 《Nature》2008,454(7203):470-477
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A superfamily of potentially oncogenic hormone receptors   总被引:43,自引:0,他引:43  
S Green  P Chambon 《Nature》1986,324(6098):615-617
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Oestrogen receptors and antagonism of steroid hormone action   总被引:11,自引:0,他引:11  
J H Clark  E J Peck  J N Anderson 《Nature》1974,251(5474):446-448
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Identification of a new class of steroid hormone receptors   总被引:54,自引:0,他引:54  
V Giguère  N Yang  P Segui  R M Evans 《Nature》1988,331(6151):91-94
The gonads and adrenal glands produce steroids classified into five major groups which include the oestrogens, progestins, androgens, glucocorticoids and mineralocorticoids. Gonadal steroids control the differentiation and growth of the reproductive system, induce and maintain sexual characteristics and modulate reproductive behaviour. Adrenal steroids also influence differentiation as well as being metabolic regulators. The effects of each steroid depend primarily on its specific receptors, the nature of which could therefore provide a basis for classification of steroid hormone action. The successful cloning, sequencing and expression of the human glucocorticoid (hGR) (ref. 1), oestrogen (hER), progesterone (hPR), and mineralocorticoid (hMR) receptors, complementary DNA, plus homologues from various species, provides the first opportunity to study receptor structure and its influence on gene expression. Sequence comparison and mutational analysis show structural features common to all groups of steroid hormone receptors. The receptors share a highly conserved cysteine-rich region which functions as the DNA-binding domain. This common segment allows the genome to be scanned for related gene products: hMR cDNA for example, was isolated using an hGR hybridization probe. In this study, using the DNA-binding domain of the human oestrogen receptor cDNA as a hybridization probe, we have isolated two cDNA clones encoding polypeptides with structural features suggestive of cryptic steroid hormone receptors which could participate in a new hormone response system.  相似文献   

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M Petkovich  N J Brand  A Krust  P Chambon 《Nature》1987,330(6147):444-450
A cDNA encoding a protein that binds retinoic acid with high affinity has been cloned. The protein is homologous to the receptors for steroid hormones, thyroid hormones and vitamin D3, and appears to be a retinoic acid-inducible trans-acting enhancer factor, suggesting that the molecular mechanisms of the effect of retinoids (vitamin A) on embryonic development, differentiation and tumour cell growth are similar to those described for other members of this nuclear receptor family.  相似文献   

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B P Moore  I A Forsyth 《Nature》1980,284(5751):77-78
Procedures, such as teat removal (thelectomy) or teat duct ligation, which prevent removal of milk, lead to rapid involution of the lactating mammary gland; performed unilaterally they have been used previously to study the biochemistry of involution, enabling a comparison of normal and involuting glands in the same animal against the same systematic hormonal environment. Both the protein hormone prolactin and the steroid hormone oestrogen are of importance in the development and function of the mammary gland. In the present experiments, female Sprague-Dawley rats were unilaterally thelectomised and the binding to the mammary gland of prolactin and oestrogen was examined through pregnancy, lactation and weaning. There was an effect of thelectomy during lactation only, when levels of both receptors increased in the intact lactating gland but failed to rise in the thelectomised, involuting gland. Capillary closure is known to occur in the mammary glands of rats after 36-48 h of milk accumulation. The rate of delivery of hormones to the tissue will be drastically reduced and it is concluded that this, rather than systemic hormone levels, is of importance in controlling receptor levels.  相似文献   

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